Rapid advances in genomic technologies are providing infectious disease researchers an unprecedented capability to study, at a genetic level, the viruses that cause disease and their interactions with infected hosts. The Broad Institute has led many technical and analytical advances that have enabled the genomic revolution and is one of the largest genome centers in the world. Our microbial genomics group has developed research programs in numerous viruses and has already sequenced over 6,500 viral strains from around the world. By leveraging the capacity and resources we have built in viral sequencing, as well as our field efforts and collaborations over the last decade, we will investigate three of the world's most important emerging infectious pathogens: Lassa Virus (LASV) and Dengue Virus (DENV), both Category A agents, and West Nile Virus (WNV), a Category B agent. These pathogens are notable for the high mortality, widespread disease and public health importance (in the US and elsewhere) they represent. Understanding how these small RNA viruses rapidly adapt to and escape from host selection pressures, including adaptive immune responses, is key to the design of viral diagnostics, vaccines and therapeutic drugs. Through our own efforts and through collaborations with clinicians and researchers, we have access to many important clinical and field samples that enable us to study not only viral evolution and spread within different geographic locations (Africa, South America and North America), but also viral adaptation within infected individuals. Rich collections of sample-associated metadata allow us to correlate viral genotype with disease severity and clinical outcome. Use of robust animal models of infection that recapitulate human disease progression will generate important insights into the pathology of LASV, DENV and WNV. Given the enzootic life cycle of these viruses, we are also investigating viral evolution and transmission within their natural hosts, which Include rodents, birds and mosquitos. Finally, we will take advantage of our existing global sample collection sites to investigate samples from patients who present symptoms similar to those caused by our diseases of study, but whose diagnoses remain unknown (FUOs, Fevers of Unknown Origin). Through these efforts we expect to better understand viral emergence and adaptation on a geographic scale as well as through the viral life cycle, from natural reservoirs to human infections. Detailed examination of viral diversity from field and clinical samples will provide remarkable insight into the dynamics of evolution and adaptation that are required for these viruses to emerge from isolated outbreaks to endemic disease with increasing health burdens worldwide.